There is growing experimental evidence that progesterone, its metabolites and other gonadal steroids such as estrogen and possibly testosterone, are effective neuroprotective agents; although the specific, physiological mechanisms by which these hormones act in the central nervous system to enhance repair are not completely understood. In addition to being a gonadal steroid, progesterone also belongs to a family of autocrine/paracrine hormones called neurosteroids. Neurosteroids are steroids that accumulate in the brain independently of endocrine sources and which can be synthesized from sterol precursors in glial cells. These neurosteroids can potentiate GABA transmission, modulate the effects of glutamate, enhance the production of myelin, reduce the expression of inflammatory cytokines and prevent release of free radicals from activated microglia.
In vivo data has demonstrated progesterone's neuroprotective effects in injured nervous systems. For example, following a contusion injury, progesterone reduces the severity of post injury cerebral edema. The attenuation of edema by progesterone is accompanied by the sparing of neurons from secondary neuronal death and improvements in cognitive outcome (Roof et al. (1994) Experimental Neurology 129:64-69). Furthermore, following ischemic injury in rats, progesterone has been shown to reduce cell damage and neurological deficit (Jiang et al. (1996) Brain Research 735:101-107). Progesterone's protective effects may be mediated thorough its interaction with GABA and/or glutamate receptors as well as its effects on inflammatory cytokines and aquaporin expression which are mediated by the intranuclear progesterone receptor.
Various metabolites of progesterone have also been suggested to have neuroprotective properties. For instance, the progesterone metabolites allopregnanolone or epipregnanolone are positive modulators of the GABA receptor, increasing the effects of GABA in a manner that is independent of the benzodiazepines (Baulieu, E. E. (1992) Adv. Biochem. Psychopharmacol. 47:1-16; Robel et al. (1995) Crit. Rev. Neurobiol. 9:383-94; Lambert et al. (1995) Trends Pharmacol. Sci. 16:295-303; Baulieu, E. E. (1997) Recent Prog. Horm. Res. 52:1-32; Reddy et al. (1996) Psychopharmacology 128:280-92). In addition, these neurosteroids act as antagonists at the sigma receptor: a receptor that can activate the NMDA channel complex (Maurice et al. (1998) Neuroscience 83:413-28; Maurice et al. (1996) J. Neurosci. Res. 46:734-43; Reddy et al. (1998) Neuroreport 9:3069-73). These neurosteroids have also been shown to reduce the stimulation of cholinergic neurons and the subsequent release of acetylcholine by excitability. Numerous studies have shown that the cholinergic neurons of the basal forebrain are sensitive to traumatic brain injury and that excessive release of acetylcholine can be more excitotoxic than glutamate (Lyeth et al. (1992) J. Neurotrauma 9(2):S463-74; Hayes et al. (1992) J. Neurotrauma 9(1):S173-87).
Following a traumatic injury to the central nervous system, a cascade of physiological events leads to neuronal loss including, for example, an inflammatory immune response and excitotoxicity resulting from the initial impact disrupting the glutamate, acetylcholine, cholinergic, GABAA, and NMDA receptor systems. In addition, the traumatic CNS injury is frequently followed by brain and/or spinal cord edema that enhances the cascade of injury and leads to further secondary cell death and increased patient mortality.
Other kinds of CNS injury can set into motion different physiological events that lead to neuronal loss. For example, ischemic injury occurs when blood flow to the CNS is interrupted. During ischemia, consumed cellular ATP usually cannot be adequately replenished in the absence of a supply of oxygen. Other physiological events associated with ischemic CNS injury include release or overexpression of proteins such as neuron-specific enolase (NSE), myelin basic protein, glial fibrillary acidic protein (GFAP), the S-100 protein, and the gamma isoform of protein kinase C (PKCg), stimulation of membrane phospholipid degradation and subsequent free-fatty-acid accumulation, cellular acidosis, glutamate release and excitotoxicity, calcium ion influx, and free radical generation.
Significant ischemia in the CNS occurs with stroke, leading to rapid cell death in the core regions of the stroke where blood flow is reduced to about 20% of normal levels. However, there is a larger area of potential injury, called the ischemic penumbra, where blood flow is reduced to a lesser extent. Cells in this region are endangered, but may not be irreversibly damaged.
Because of limitations in current therapies for CNS injuries as described above, improved methods for treating traumatic and ischemic CNS injury are needed.